title: A critical role for Lyn kinase in strengthening endothelial integrity and barrier function.
abstract: The Src family kinases (SFKs) c-Src and Yes mediate vascular leakage in response to various stimuli including lipopolysaccharide (LPS) and vascular endothelial growth factor (VEGF). Here, we define an opposing function of another SFK, Lyn, which in contrast to other SFKs, strengthens endothelial junctions and thereby restrains the increase in vascular permeability. Mice lacking Lyn displayed increased mortality in LPS-induced endotoxemia and increased vascular permeability in response to LPS or VEGF challenge compared with wild-type littermates. Lyn knockout mice repopulated with wild-type bone marrow-derived cells have higher vascular permeability than wild-type mice, suggesting a role of endothelial Lyn in the maintenance of the vascular barrier. Small interfering RNA-mediated down-regulation of Lyn disrupted endothelial barrier integrity, whereas expression of a constitutively active mutant of Lyn enhanced the barrier. However, down-regulation of Lyn did not affect LPS-induced endothelial permeability. We demonstrate that Lyn association with focal adhesion kinase (FAK) and phosphorylation of FAK at tyrosine residues 576/577 and 925 were required for Lyn-dependent stabilization of endothelial adherens junctions. Thus, in contrast to c-Src and Yes, which increase vascular permeability in response to stimuli, Lyn stabilizes endothelial junctions through phosphorylation of FAK. Therefore, therapeutics activating Lyn kinase may strengthen the endothelial barrier junction and hence have anti-inflammatory potential.
authors.affiliation: Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY;
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhang
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Welch
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Vogel
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D022005:Adherens Junctions / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases